[en] Endoplasmic reticulum (ER) stress is a central actor in the physiopathology of insulin resistance (IR) in various tissues. The subsequent unfolded protein response (UPR) interacts with insulin signaling through inositol-requiring 1alpha (IRE1alpha) activation and tribbles homolog 3 (TRB3) expressions. IRE1alpha impairs insulin actions through the activation of c-Jun N-terminal kinase (JNK), and TRB3 is a pseudokinase inhibiting Akt. In muscle cells, the link between ER stress and IR has only been demonstrated by using chemical ER stress inducers or overexpression techniques. However, the involvement of ER stress in lipid-induced muscle IR remains controversial. The aim of the study is to test whether palmitate-induced IRE1alpha signaling and TRB3 expression disturb insulin signaling in myogenic cells. C2C12 myotubes were exposed to palmitate and then stimulated with insulin. siRNA transfection was used to downregulate TRB3 and IRE1alpha. Palmitate increased TRB3 expression, activated IRE1alpha signaling, and reduced the insulin-dependent Akt phosphorylation. Knocking down TRB3 or IRE1alpha did not prevent the inhibitory effect of palmitate on Akt phosphorylation. Our results support the idea that ER stress is not responsible for lipid-induced IR in C2C12 myotubes.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Pierre, Nicolas ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Fernandez-Verdejo, Rodrigo
Regnier, Pauline
Vanmechelen, Simon
Demeulder, Benedicte
Francaux, Marc
Language :
English
Title :
IRE1alpha and TRB3 do not contribute to the disruption of proximal insulin signaling caused by palmitate in C2C12 myotubes.
Publication date :
2016
Journal title :
Cell Biology International
ISSN :
1065-6995
eISSN :
1095-8355
Publisher :
Wiley-Blackwell, New York, United States - New York
Volume :
40
Issue :
1
Pages :
91-9
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2015 International Federation for Cell Biology.
An D, Lessard SJ, Toyoda T, Lee MY, Koh HJ, Qi L, Hirshman MF, Goodyear LJ (2014) Overexpression of TRB3 in muscle alters muscle fiber type and improves exercise capacity in mice. Am J Physiol Regul Integr Comp Physiol 306: R925–33.
Cnop M, Foufelle F, Velloso LA (2012) Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 18: 59–68.
Du K, Herzig S, Kulkarni RN, Montminy M (2003) TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300: 1574–7.
Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29: 42–61.
Hage Hassan R, Hainault I, Vilquin JT, Samama C, Lasnier F, Ferre P, Foufelle F, Hajduch E (2012) Endoplasmic reticulum stress does not mediate palmitate-induced insulin resistance in mouse and human muscle cells. Diabetologia 55: 204–14.
Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140: 900–17.
Iynedjian PB (2005) Lack of evidence for a role of TRB3/NIPK as an inhibitor of PKB-mediated insulin signalling in primary hepatocytes. Biochem J 386: 113–8.
Koh HJ, Toyoda T, Didesch MM, Lee MY, Sleeman MW, Kulkarni RN, Musi N, Hirshman MF, Goodyear LJ (2013) Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle. Nat Commun 4: 1871.
Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18: 716–31.
Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H (2005) TRB3, a novel ER stress-inducible gene, is induced via ATF4- CHOP pathway and is involved in cell death. EMBO J 24: 1243–55.
Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306: 457–61.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313: 1137–40.
Pal M, Wunderlich CM, Spohn G, Bronneke HS, Schmidt- Supprian M, Wunderlich FT (2013) Alteration of JNK-1 signaling in skeletal muscle fails to affect glucose homeostasis and obesity-associated insulin resistance in mice. PLoS ONE 8: e54247.
Pierre N, Barbe C, Gilson H, Deldicque L, Raymackers JM, Francaux M (2014) Activation of ER stress by hydrogen peroxide in C2C12 myotubes. Biochem Biophys Res Commun 450: 459–63.
Rieusset J, Chauvin MA, Durand A, Bravard A, Laugerette F, Michalski MC, Vidal H (2012) Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protectmuscle cells frompalmitate-induced insulin resistance. Biochem Biophys Res Commun 417: 439–45.
Salvado L, Coll T, Gomez-Foix AM, Salmeron E, Barroso E, Palomer X, Vazquez-Carrera M (2013) Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPKdependent mechanism. Diabetologia 56: 1372–82.
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664–6.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034.
Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nalsen C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, Gustafsson IB, Storlien LH (2001) Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia 44: 312–9.
Yuzefovych L, Wilson G, Rachek L (2010) Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Endocrinol Metab 299: E1096–105.
Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454: 455–62.
Zhang Y, Li F, Liu S, Wang H, Mahavadi S, Murthy KS, Khalili K, Hu W (2012) MEKK1-MKK4-JNK-AP1 pathway negatively regulates Rgs4 expression in colonic smooth muscle cells. PLoS ONE 7: e35646.